The specialized ends of chromosomes, or telomeres, protect eukaryotic organisms from DMA degradation, chromosomal fusion, and the activation of DNA repair mechanisms. Telomere maintenance in dividing cells requires the enzyme telomerase. The role that telomeres and telomerase play in regulating the proliferate capacity of neural stem cells, both neuronal and oligodendrocyte precursor cells (OPCs), had been the primary focus of my post-doctoral research. The project in this Research Career Development Award application will build on my earlier work showing that OPC growth arrest and differentiation is coupled to telomerase down-regulation. This project hypothesizes that the failure in remyelination of multiple sclerosis may be due in part to depletion of OPC pools resulting from successive rounds of demyelination and remyelination, and that OPC proliferation is limited by telomerase deficiency and telomere shortening. The Specific Aims of this proposal are: 1) To examine whether telomerase and telomere length play a role in OPC proliferation and remyelination following demyelinating injury in a mouse model of multiple sclerosis; 2) To determine whether telomerase over-expression or inhibition affects OPC proliferation and differentiation in cell culture; and 3) To determine whether OPC proliferation is associated with telomere shortening and whether telomere loss triggers replicative senescence or apoptosis. The long-term goals of this study are to determine whether telomerase can be used to enhance oligodendrocyte growth and remyelination, which might be useful in the treatment of multiple sclerosis. This Award would help me achieve these goals as I undertake the next stage of my career as laboratory head and attending neurologist at Weill Medical College of Cornell University. It would provide me with the support to continue my experiments, learn new research skills, and dedicate the time needed to develop my career, both as a researcher and as a clinician. [unreadable] [unreadable] [unreadable]